In the present study we provide evidence of neuronal and microglial MHC-I expression in epileptogenic glioneuronal lesions. The neuronal expression of MHC-I was, however, only detected in FCD II, but not in FCD I specimens or in the perilesional region (despite the absence of significant differences in seizure frequency and duration). Interestingly, MHC-I expression in neurons was significantly higher in FCD IIb compared to FCD IIa and the large majority of balloon/giant cells did not express detectable levels of MHC-I. These observations confirm the difference between FCD I and II
, suggest some differences between IIa and IIb and indicate that induction of MHC-I is not simply an effect of seizure activity.
Several studies demonstrate that expression of MHC-I can be upregulated in glia and neurons in response to different types of challenges, including injury, infections (chronic and acute), central administration of endotoxins and exposure to different cytokines (
[28–33] reviewed in
). Cytokines have been show to differentially regulate MHC-I induction in neurons
[31, 34, 35]. Previous studies have demonstrated prominent expression of components of the IL-1R/TLR signaling pathways in neuronal cells in epileptogenic glioneuronal lesions
[6, 26, 27, 36]. Signaling through these pathways leads to activation of the transcription factor, nuclear factor-kappa B (NF-κB)
. Interestingly, it has been suggested that activation of NF-κB plays a role in induction of MHC-I
[38, 39]. Thus, NF-κB-dependent mechanisms of regulation may contribute to the more prominent MHC-I expression detected in FCD II (associated with consistent activation of IL-1R/TLR signaling pathways
) compared to FCD I.
Endogenous peptides presented by MHC-I molecules (called MHC-I peptides (MIPs) or the immunopeptidome) represent the key to self/non-self-discrimination by cells of the immune system. In this respect, a recent study confirmed previous observations indicating that the immune system is tolerant to MIPs expressed at physiological levels but may promote immune responses towards self MIPs present in excessive amounts
[40, 41]. This may be important in the context, of the suggestion that neuronal MHC-I expression mediates removal of dysfunctional neurons
. The study by Caron et al. also suggests that changes in mTOR signaling can affect the expression of MHC-I and the repertoire of MIPs presented by MHC-I
. These observations highlight the complexity of MHC-I regulation and indicate the need for further analysis of the effect of mTOR modulation in lesions (such as FCD II, TSC and GG) in which this pathway is involved. Interestingly, a recent study suggests a novel viral etiology for FCD IIB
, which could explain the constitutive activation of mTOR, as well as the induction of MHC-I, in this focal malformation of cortical development.
Interestingly, neuronal MHC-I expression has been reported in Rasmussen’s encephalitis and it has been suggested that it plays a critical role in antigen-specific cytotoxicity
. MHC-I expression is necessary for antigen-specific cytotoxicity mediated by CD8+ lymphocytes
. In this context, we also detected CD8+ T lymphocytes with GrB in FCD IIB and TSC specimens in the vicinity of neurons. The possible contribution of a MHC-I restricted immune response to neuronal injury, occurring in patients with developmental pathologies and intractable epilepsy
[18, 44], requires further investigation.
MHC-I was also was found to be expressed in reactive microglial cells. Upregulation in microglial cells has been shown in both multiple sclerosis (MS)
 and Rasmussen’s encephalitis
[8, 9]. Interestingly, the microglial expression of MHC-I was significantly higher in FCD II compared to FCD I, reflecting the more prominent activation of microglial cells observed in FCD II specimens
. Moreover, MHC-I expression in microglia correlated positively with the duration of epilepsy, suggesting that the upregulation of MHC-I in these cells may also occur later in epileptogenesis.
Astrocytes did not display MHC-I immunoreactivity. Expression of MHC-I in astrocytes has also not been observed in MS lesions
. Thus upregulation of MHC-I in astrocytes appears to represent a specific feature of Rasmussen’s encephalitis and an MHC-I restricted T-cell response has been suggested as critically contributing to the occurrence of the astrocytic degeneration observed in this pathology
MHC-I expression was not detected in balloon cells in FCD IIb and in the large majority of giant cells in TSC. Interestingly, expression of MHC-I has been detected in the giant cells from different types of TSC-associated brain lesions in fetal cases ranging from 23 to 34 gestational weeks (GW)
, indicating developmental changes in the phenotype of giant cells. MHC-I expression in these cells early in development may reflect their role as antigen-presenting cells and may account for the dynamic changes occurring early in development in TSC lesions.
We did not detect changes in the expression levels of MHC-I in endothelial cells within the different lesions examined. However, lesions (FCD IIB, TSC and GG) with prominent inflammatory changes and MHC-I upregulation in neurons and microglia displayed evidence of alterations in blood–brain barrier permeability, with albumin extravasation and uptake in astrocytes. These observations confirm previous findings for TSC
, highlighting its similarity to FCD IIB and the differences with FCD I.
Our findings distinguish type I from type II FCD and indicate a prominent upregulation of MHC-I in neurons and microglial cells as part of the immune response occurring in epileptogenic glioneuronal lesions, such as FCD II, TSC and GG.